TY - JOUR
T1 - IFNγ-Dependent Tissue-Immune Homeostasis Is Co-opted in the Tumor Microenvironment
AU - Nirschl, Christopher J.
AU - Suárez-Fariñas, Mayte
AU - Izar, Benjamin
AU - Prakadan, Sanjay
AU - Dannenfelser, Ruth
AU - Tirosh, Itay
AU - Liu, Yong
AU - Zhu, Qian
AU - Devi, K. Sanjana P.
AU - Carroll, Shaina L.
AU - Chau, David
AU - Rezaee, Melika
AU - Kim, Tae Gyun
AU - Huang, Ruiqi
AU - Fuentes-Duculan, Judilyn
AU - Song-Zhao, George X.
AU - Gulati, Nicholas
AU - Lowes, Michelle A.
AU - King, Sandra L.
AU - Quintana, Francisco J.
AU - Lee, Young suk
AU - Krueger, James G.
AU - Sarin, Kavita Y.
AU - Yoon, Charles H.
AU - Garraway, Levi
AU - Regev, Aviv
AU - Shalek, Alex K.
AU - Troyanskaya, Olga G.
AU - Anandasabapathy, Niroshana
N1 - Funding Information:
Doug Hilton and Warren Alexander generously provided SOCS2−/− mice. The laboratories of Arlene Sharpe and Charles Drake provided B16-OVA and EL4-OVA tumor lines. We are grateful to Celldex for recombinant Flt3L, Steve Reed and Infectious Disease Research Institute for GLA, and Dev Manoli for critical reading of the manuscript. C.N. was supported by a 5T32AR007098 Dermatology Training Grant. B.I. was supported by the DFCI Wong Family Award for Translational Cancer Research. N.G. was supported by a T32GM07739 MSTP Grant. A.K.S. was supported by the Searle Scholars Program, the Beckman Young Investigator Program, and the NIH New Innovator Award DP2OD020839. N.A., Y.L., and C.N. were supported by the Melanoma Research Alliance-BWH Department of Dermatology combined grant, the Cancer Research Institute, the Klarman Family Foundation, and the National Institute of Arthritis and Musculoskeletal and Skin Disease R01AR070234 and K23 AR063461 (to N.A). A.R. is on the scientific advisory board for ThermoFisher Scientific, Syros Pharmaceuticals, and Driver Group. J.G.K. is a consultant for Biogen. L.G. was a consultant for Foundation Medicine, Novartis, Boehringer Ingelheim, Eli Lilly, an equity holder in Foundation Medicine, and a member of the scientific advisory board at Warp Drive. L.G. also received grant support from Novartis. L.G. is now an employee of Eli Lilly and Company.
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/6/29
Y1 - 2017/6/29
N2 - Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment.
AB - Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment.
KW - IFNγ
KW - dendritic cells
KW - differentiation
KW - homeostasis
KW - immunotherapy
KW - melanoma
KW - suppressor-of-cytokine-signaling 2 (SOCS2)
KW - tissue mononuclear phagocytes
KW - tolerance
KW - tumor microenvironment
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U2 - 10.1016/j.cell.2017.06.016
DO - 10.1016/j.cell.2017.06.016
M3 - Article
C2 - 28666115
AN - SCOPUS:85021662906
SN - 0092-8674
VL - 170
SP - 127-141.e15
JO - Cell
JF - Cell
IS - 1
ER -